Acid 1b Research Articles

A Convenient Method for the Preparation of Alkanolamides

Long chain alkanolamides have attracted considerable interest because of their intrinsic amphiphilic properties. They are frequently used as a surfactant for cosmetics and pharmaceutical use. In the course of the synthesis of alkanolamides, control of chemoselective amide formation over competing O-acylation of neighboring hydroxyl groups plays a key step. Several methods have been developed which include a few enzymatic synthesis and the reaction of carboxylic acid with amino alcohols by the aid of N-ethoxy1-ethoxy-dihydroquinone (EEDQ) in ethanol reflux condition. However, these known methods have drawbacks for example narrow application scope in enzymatic reaction, longer reaction time and harsh reaction condition. Recently, we have reported that chemoselective N-acylation of amino alcohols promoted by magnesium oxide in aqueous organic solution. Although the use of this method was successful in many cases, preparation of acid chloride is not always easy so there is still a strong need for more convenient amidation method of amino alcohols. Now we report a useful procedure for the efficient and chemoselective amidation of hydrophilic amino alcohols with mixed anhydride generated from carboxylic acid and ethylchloroformate (Scheme 1). Treatment of benzoic acid 1a with ethylchloroformate (1.1 equiv) in the presence of N-methylmorpholine (1.1 equiv) in THF gave mixed anhydride, which subsequently reacted with tris(hydroxymethyl)aminomethane 3a in DMF and TEA (1.1 equiv) to give alkanolamide 4a in 85% yield (entry 1 in Table 1). The formation of by-products such as O-acylated and N, O-diacylated derivatives have not been observed in HPLC analysis. After the disappearance of mixed anhydride checked by TLC analysis, DMF was evaporated in vacuo. The residue of reaction mixture was extracted with ethyl acetate, washed with water. The organic layer was analyzed by HPLC. As shown in Figure 1, small amount of benzoic acid were detected without by-products. Benzoic acid was easily separated by flash chromatography. As an additive for the synthesis of mixed anhydride, TEA as well as N-methylmorpholine was effective. Of solvents tested, THF and ether were suitable. Using aliphatic carboxylic acid 2b, alkanolamide 4b was also obtained in high yield (entry 2). Further, this method was successfully extended to other acids containing acid or base-sensitive groups such as cyclic disulfide, ester and acetate (entry 3, 4 and 5). In all cases, byproducts that are usually formed in the reaction of acid chlorides with amino alcohols were not detected. Preferential amine selectivity can be explained by assuming low electrophilicity of mixed anhydride comparing with acid chloride. Because of its low electrophilicity, more nucleophilic amino groups may only react with mixed anhydride. The reaction also worked well for the other hydrophilic amine such as ethanolamine, DL-serine methyl ester and diethanolamine. The desired alkanolamides 4f, 4g and 4h

Novel Water‐Soluble Poly(m‐benzamide)s: Precision Synthesis and Thermosensitivity in Aqueous Solution

AbstractSummary: Chain‐growth polycondensations of 3‐aminobenzoic acid methyl esters 1a and 1b, bearing a tri‐ or tetra(ethylene glycol) methyl ether unit on the amino group, respectively, were carried out with lithium hexamethyldisilazide (LiHMDS) as a base and phenyl 4‐methylbenzoate (2) as an initiator in THF at 0 °C. The poly(m‐benzamide)s obtained in the presence of N,N,N′,N′‐tetramethylethylenediamine (TMEDA) possessed narrow molecular weight distributions ($\overline M _{\rm w} /\overline M _{\rm n}$ < 1.2) with molecular weights that were determined by the feed ratios of [1]0/[2]0. Poly1a and poly1b were each soluble in water and exhibited a lower critical solution temperature (LCST) in water. Furthermore, the phase separation in water depended on the length of the oligo(ethylene glycol) side chain and on the molecular weight and molecular weight distribution of poly1.Thermally sensitive water‐soluble poly(m‐benzamide)s.magnified imageThermally sensitive water‐soluble poly(m‐benzamide)s.

Reaction of phthalimido alkyl acids with isopropylamine: synthesis, anti-inflammatory and antinociceptive properties

Phthalimido alkyl acids 3-phthalimidopropionic acid (2a) and 4-phthalimidobutyric acid (2b) were treated with isopropylamine at room temperature using different solvents (dimethylformamide, dichloromethane and methanol) as the reaction medium and afforded 3-benzamido-propionic acid ‐2-(2methylethyl)-carboxamide (3), 2-benzamido-2-methylethane-2-(2-methylethyl)-carboxamide (4), and 4benzamido-butyric acid ‐2-(2-methylethyl)- carboxamide (5). Compound 4 was a dimmer that was least expected. Compounds 3, 4 and 5 were evaluated for antinociceptive property using acetic acid-induced writhing test. 4 exhibited the highest analgesic effect at 80 mg/kg it caused 88 % inhibition and was more pronounced than the reference drugs (indomethacin, acetylsalicylic acid and paracetamol), 3 and 5. The anti-inflammatory activity of the compounds was also screened using carrageenan- induced rat paw oedema assay and 4 showed higher activity than others except the reference drug. The effects were dose-dependent.

Synthesis of (2S,3S)-[3-2H1]-4-methyleneglutamic acid and (2S,3R)-[2,3-2H2]-4-methyleneglutamic acid

(2S,3S)-[3-(2)H1]-4-Methyleneglutamic acid 1a and (2S,3R)-[2,3-(2)H2]-4-methyleneglutamic acid 1b have been synthesised for use in biosynthetic and metabolic studies.

A Pair of Novel Cytotoxic Polyprenylated Xanthone Epimers from Gamboges

Two new polyprenylated xanthone epimers were isolated from gamboges of Garcinia hanburyi, and identified by detailed spectroscopic analysis as 30-hydroxygambogic acid (2a) and its (2S)-epimer 30-hydroxyepigambogic acid (2b). Both compounds exhibited significant cytotoxicities against the human leukemia K562/S and the corresponding doxorubicin-resistant K562/R cell lines (Table 2).

Synthesis and characterization of palladium(ii) complexes with new diphosphonium-diphosphine and diphosphine ligands. Production of low molecular weight alternating polyketones via catalytic CO/ethene copolymerisation

The bis-cationic diphosphonium-diphosphine 6,7-di(di-2-methoxyphenyl)phosphinyl-2,2,4,4-tetra(di-2-methoxyphenyl)-2 lambda 4,4 lambda 4-diphosphoniumbicyclo[3.1.1]heptane-bis(PF6) ((o-MeO-PCP)(PF6)2) and the diphosphine rac-2,4-bis((di-2-methoxyphenyl)phosphino)pentane (rac-o-MeO-bdpp) have been synthesized. Both ligands have been employed to coordinate PdCl2 and Pd(OAc)2 to give [PdCl2(o-MeO-PCP)](PF6)2 (1a), PdCl2(rac-o-MeO-bdpp) (1b), [Pd(OAc)2(o-MeO-PCP)](PF6)2 (2a) and Pd(OAc)2(rac-o-MeO-bdpp) (2b). The ligands and complexes have been fully characterized in solution by multinuclear NMR spectroscopy. In addition, 1a and 1b have been authenticated by single crystal X-ray structure analyses. The Pd(II) complexes 1a and 1b have been employed as catalyst precursors for the CO/ethene copolymerisation in water-acetic acid mixtures, while 2a and 2b have been tested in methanol in the presence of p-toluenesulfonic acid. Irrespective of the reaction media, perfectly alternating polyketones were obtained in excellent yields and with number-average molecular weights ranging from 7.1-13.9 kg mol(-1) with the diphosphonium-diphosphine catalysts and from 37.2-48.2 kg mol(-1) with the diphosphine catalysts.

Phosphorodiamidic Acid as a Novel Structural Motif of Brønsted Acid Catalysts for Direct Mannich Reaction ofN-Acyl Imines with 1,3-Dicarbonyl Compounds

Phosphorodiamidic acid 1 was developed as an efficient Bronsted acid catalyst for the direct Mannich reaction of N-acyl imines with 1,3-dicarbonyl compounds. Phosphorodiamidic acids were proposed as a novel structural motif of enantioselective ­Bronsted acid catalysts because they possess unique features, including the capability of introducing various substituents to the nitrogen atoms and the preparation from readily available chiral diamines in a short step. We demonstrated that chiral phosphorodiamidic acid 1b derived from binaphthalene bis(sulfonamide) functioned as an enantioselective catalyst to give the Mannich product in an optically active form.

Synthesis of 2H‐Chromeno[4,3‐b]pyridine‐2,5(1H)‐diones and Related Heterocycles via the Erlenmeyer—Ploechl Reaction.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of 7,11-diaryl-3-oxo (or thioxo)-2,4-diazaspiro[5.5]undecane-1,5,9-triones, Part I

Spiro compounds 7,11-diaryl-2,4-diazaspiro[5.5]undecane-1,3,5,9-tetraones 3a–e and 7,11-diaryl-3-thioxo-2,4-diazaspiro[5.5]undecane-1,5,9-triones 3f–j were prepared from the reaction of 1,5-diaryl-1,4-pentadien-3-ones 2a–f with barbituric acid (1a) and 2-thiobarbituric acid (1b). The structures of the products were confirmed by UV, IR, 1H and 13C NMR, MS and elemental analysis.

Synthesis and properties of dinitrobenzamido-TEMPO derivatives

Chloro-3,5-dinitrobenzoic acid (1a) and 2-chloro-3,5-dinitrobenzoic acid (1b) were converted into the corresponding acid chlorides (2a and 2b) and these were reacted first with an equimolar amount of 4-amino-2,2,6,6-tetramethylpiperidine-N-oxyl radical (4-amino-TEMPO) to afford monoradicals 3a, 3b, 5a, and 5b and then either (i) with methoxyamine to yield hetero-diradicals 6a and 6b, or (ii) with a second mole of 4-amino-TEMPO to afford homo-diradicals 4a and 4b. The reaction of 3a with 1,3-bis(aminooxy)propane gave the homo-diradical 7a. These reaction products are stable mono- or di-radicals as evidenced by their ESR spectra at various temperatures. The above reaction products can participate as oxidizers in redox reactions, and they afford deep-colored anions with inorganic or organic bases.

Synthesis of 2H‐chromeno[4,3‐b]pyridine‐2,5(1H)‐diones and related heterocycles via the erlenmeyer‐ploechl reaction

Abstract1,2‐Dihydro‐5H‐[1]benzopyrano[4,3‐b]pyridine‐2,5‐diones 4a‐j were synthesized from 4‐alkylamino‐coumarin‐3‐carbaldehydes 1 and 5(4H)‐oxazolinones (azalactones) derived from N‐acetylglycine (2a) and hippuric acid (2b). The intermediates 3 (3j isolated only) underwent spontaneous recyclization via opening of the azalactone and successive formation of the fused 2‐pyridones 4. Attempts to synthesize the selected 2H‐chromeno[3,4‐f]‐1,7‐naphthyridine 6 by Vilsmeier reaction of 4e failed. Instead, N‐deacetylation took place, followed by formylation of the amino group to the formamidine 7a. In addition, pyranopyridine 9a was obtained by condensation of the 3‐formyl‐2‐pyridone 8 with the azalactone derived from 2a and acetic anhydride.

Antibacterial triterpenes from Syzygium guineense (Myrtaceae)

Antibacterial bioassay-guided fractionation of Syzygium guineense leaf extracts afforded 10 triterpenes, namely betulinic acid 1, oleanolic acid 2, a mixture of 2-hydroxyoleanolic acid 3a, 2-hydroxyursolic acid 3b, arjunolic acid 4a, asiatic acid 4b, a mixture of terminolic acid 5a, 6-hydroxyasiatic acid 5b, and a mixture of arjunolic acid 28-β-glucopyranosyl ester 6a and the asiatic acid 28-β-glucopyranosyl ester 6b. Isolated compounds were submitted to an antibacterial assay system against gram-positive and -negative bacteria and human pathogen bacteria. Compounds 4a and 4b showed the most significant antibacterial activity against Escherichia coli, Bacillus subtilis and Shigella sonnei. The fraction 5a– 5b was the least active, whereas compounds 1, 2 and the mixtures of 3a– 3b and 6a– 6b were inactive in the assays.

Cis-Dichloroplatinum (II) complexes with aminomethylnicotinate and -isonicotinate ligands

6-Aminomethylnicotinic acid ( 1a) and 2-aminomethylisonicotinic acid ( 1b) were each reacted with K 2PtCl 4 in aqueous 1 M HCl to give the corresponding N, N-chelated cis-dichloroplatinum(II) complexes 2. These were converted into amides 3 via their mixed anhydrides by treating them first with ethyl chloroformate and then with the respective 1° or 2° amine. The analogous 6-aminomethylnicotinic acid ester complexes 7 were obtained by reaction of the preformed ligands with K 2PtCl 4.

Novel Pyrazole Derivatives as Potential Promising Anti‐inflammatory Antimicrobial Agents

Four series of 1H-pyrazole derivatives have been synthesized. The first series was synthesized starting by condensing the hydrazine derivatives 1a-d with 4-(1-ethoxycarbonyl-2-oxopropyl)azobenzoic acid 2a in ethanol or glacial acetic acid to generate the corresponding pyrazoline derivatives 3a-d. Likewise, heating 1a-d with 4-(1-acetyl-2-oxopropyl)azobenzoic acid 2b gave rise to the pyrazole derivatives 4a-d. Similarly, reaction of 1a-d with ethyl 2-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylazo)-3-oxobutanoate 2c or 3-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl azo)pentane-2,4-dione 2d in ethanol or glacial acetic acid led to the corresponding pyrazoline derivatives 5a-d or pyrazole derivatives 6a-d. The newly synthesized compounds were evaluated for their anti-inflammatory-antimicrobial activities. In addition, the ulcerogenic and acute toxicity profiles were determined. Compound 6c, proved to be the most active anti-inflammatory-antimicrobial agent in the present study with a good safety margin and no ulcerogenic effect.

Electrooxidation of 4-methylcatechol in the presence of barbituric acid derivatives

Electrooxidation of 4-methylcatechol ( 1) in the presence of 1,3-dimethylbarbituric acid ( 2a) and 1,3-diethylthiobarbituric acid ( 2b) as nucleophiles has been studied in detail by cyclic voltammetry and controlled-potential coulometry. The results indicate that 1 can be oxidized to its related o-benzoquinone ( 1a) and without conversion to its quinone methide tautomeric form, via an ECEC mechanism pathway, is converted to barbiturate derivatives ( 5a– b). The electrochemical synthesis of 5a– b have been successfully performed in one-pot in an undivided cell.

Regioselective acylation of several polyhydroxylated natural compounds by Candida antarctica lipase B

Regioselective acylation of four polyhydroxylated natural compounds, deacetyl asperulosidic acid (1), asperulosidic acid (2), puerarin (3) and resveratrol (4) by Candida antarctica Lipase B in the presence of various acyl donors (vinyl acetate, vinyl decanoate or vinyl cinnamoate) was studied. Compounds 1, 2 and 4 were regioselectively acetylated with vinyl acetate to afford products, 3′-O-acetyl-10-O-deacetylasperulosidic acid (1a), 3′,6′-O-diacetyl-10-O-deacetylasperulosidic acid (1b), 3′-O-acetylasperulosidic acid (2a), 3′,6′-O-diacetylasperulosidic acid (2b), 4′-O-acetylresveratrol (4a), respectively, with yields of 22 to 50%, while reactions with vinyl decanoate and vinyl cinnamoate were slow with lower yields. Compound 3 was readily acylated with all three acyl donors and quantitatively converted to products 6″-O-acetylpuerarin (3a), 6″-O-decanoylpuerarin (3b), 6″-O-cinnamoylpuerarin (3c), respectively. The structures of these acylated products were determined by spectroscopic methods (MS and NMR).

The Antileukotrienic Derivatives and Homologues of [(Quinolin-2-ylmethoxy)sulfanyl]benzoic Acids with Reduced Lipophilicity

A series of ({[(quinolin-2-ylmethoxy)phenyl]sulfanyl}phenyl)acetic acids 2 and S-oxidized derivatives of {[(quinolin-2-ylmethoxy)phenyl]sulfanyl}benzoic acids 3 were prepared and their antileukotrienic and antiasthmatic activities evaluated. Regression analysis led to the conclusion that the antileukotrienic activities of compounds 2 correspond to the relationships between these activities and lipophilicity, derived for the previously synthesized series of substituted (arylsulfanyl)benzoic acids 1A, 1B and 1C. Acids 3 are outliers from these relationships, probably due to a somewhat different mechanism of action. A higher antiasthmatic activity was observed in some [(arylsulfanyl)phenyl]acetic acids 2 in comparison with the corresponding analogs bearing the (arylsulfanyl)benzoic acid moiety. The inhibition of 5-lipoxygenase activated protein (FLAP) was determined for these compounds, and the influence of the direct inhibition of LTB4 biosynthesis is discussed to explain the differences in the antiasthmatic effect of the compounds under study.

An Improved Preparation of N 2‐tert‐Butoxycarbonyl‐ and N 2‐Benzyloxy‐carbonyl‐(S)‐2,4‐diaminobutanoic Acids

Utilizing N‐benzyloxycarbonyl‐ (1a) and N‐tert‐butoxycarbonyl‐(S)‐glutamine (1b), a highly efficient and practical method for the synthesis of N 2‐benzyloxycarbonyl‐ and N 2‐tert‐butoxycarbonyl‐(S)‐2,4‐diaminobutanoic acids (2a and 2b) has been developed. Reaction of (S)‐glutamine derivatives with iodosobenzene diacetate in a mixture of THF‐water at 4°C afforded selectively protected (S)‐2,4‐diaminobutanoic acids in good yields.

Synthesis of α-substituted iminodiacetate ligands: α-hexadienyl derivatives for the selection of lipoxygenase mimics

Derivatives of iminodiacetic acid (IDA) are important as ligands for metal ions, having numerous applications in separations, sensing, catalysis and medicine. This report describes the preparation of two types of IDA derivatives ( 1 , 2 ) that could be covalently attached to a polymer or protein surface via a variable length spacer chain. The parent compounds 1 (R′=H) were easily prepared via N-alkylation of dimethyl iminodiacetate with esters of 6-bromo-hexanoic acid and subsequent selective ester hydrolysis. Metal complexes of IDA derivatives having an α-dienyl side chain are required for the selection of histidine-rich proteins with potential lipoxygenase activity. The α-hexadienyl side chain of IDA derivative 2 was selectively introduced in the reaction of (2,4-hexadienyl acetate)Fe(CO) 3 with a glycine-derived TMS–enol ester. Subsequent demetallation, followed by N-carboxymethylation, N-deacylation, N-alkylation with a trichloroethyl 6-halohexanoate, and TCE–ester cleavage provided the desired α-hexadienyl IDA derivative 2 . Amide formation with IDA acid 1b demonstrates the feasibility of conjugating the IDA ligands to polymers and proteins while Ni(II)-complexation with the derived IDA triacid 1e shows the complexing ability of the tethered IDA ligand.

Synthesis of New Optically Active and Racemic Phenylsuccinamic Acids

The synthesis, isolation, and characterization of new (S)-(+)- and racemic phenylsuccinamic acids, obtained from the reaction of (S)-(+)-phenylsuccinic anhydride (1) with five different primary amines (2a-e) is described.Ring opening of anhydride 1 led to the formation of two isomeric phenylsuccinamic acid products with the phenyl substituent β to the amide function being the preferred product. Complete racemization occurred with all of the α-phenylsuccinamic acids (3a-e) and β-phenylsuccinamic acids 4b and 4c. However, β-phenylsuccinamic acids 4a, 4d, and 4e were found to be optically active.